US2674621A - Synthesis of compounds having vitamin a activity - Google Patents

Description

Patented Apr. 6, 1954 c UNITED STATES T OFFICE SYNTHESIS OF COMPOUNDS HAVING VITAMIN A ACTIVITY William Oroshnik, 'Plainfield, Nr iLy-assignor =to Ortho Pharmaceutical Corporation a corporation of New Jersey No Drawing. Application October 3, 1947, SerialJNo. 777;862

15 Claims. (01. 2604488) 1 '2 This invention relates to compositions of matan etheror a 154 chlorohydrin o1 isoprene acter and to methods'for preparing the same. This cording to the followin equation: invention particularly relates to compounds which are derivatives of a-ethynyl-fi-ionol and to methods of preparing the said derivatives. 5

It is an object of this invention to prepare compounds to be used as intermediates in the preparation of compounds having vitamin A activity.

It is another object-of this invention to pre- CH3 Cm CH3 pare compounds having the same number of car- 1 l bon atoms and the same configuration with re- CH=CH C=C""CHC=CH OHWOCH spect to carbon atoms as vitamin A ethers or O esters.

It is another obj ect'of this invention to prepare H1 hydroxy compounds having the same number of The acetylenic compound could not be distilled carbon atoms and the same configuration with ith t dehydration because of impurities which respect to carbon atoms as vitamin A ethers-or were nt, Th reduction product of the CH: C

esters. acetylenic compound could be converted to a It is still another object of this invention to compound having vitamin A activity by a simulp pare a yd xy p u d having t some tane'ous rearrangement'and dehydration. number of carbon atoms and the same config- As" shown in the publication cited above, the uration with respect to carbon atoms as vitainventor has discoveredcertain new derivatives min A or a vitamin A ether'which has vitamin A of e-ethynyl-p-ionol and a method 'for their activity and rk d Stability to oxidation. preparation. It has now been further discovered It is another and further object of this inventhat the said derivatives of u-ethynyl-fl-ionol tion to prepare compounds having the same maybe prepared in excellent yields and that they number of carbon atoms and the same conmay be prepared free from impurities and stable figuration withirespeot o C r atoms as Vitato distillation. It-has also been discovered that min A esters or ethers and the same number of 3 esters of -a'1,4 ha'lohy'drin of isoprene, as-well as y ogen atoms as vitamin A esters or ethers. the correspondingethers, may be used in the re- It is another object of this inventionto prepare action with a-ethynyl-fl-ionol and that thereby compounds having v tam A c tynew and analogous derivatives having a termi- Other objects of this invention will be apparnal st group may be obtained. entfrom th d s p f lowin and from the It has been *further discovered that the said appended claims. derivatives of a-ethynyl-fi-ionol may be isomer- In the Journal of the American Chemical ized and dehydrated or dehydrated and isomer- Society, vol me 67, page 1627 (1945), the inized to form additionalderivatives which have ventor disclosed that certain derivatives of vitaminAactivity.

or-ethynyl-p-ionol have value as intermediates in 40 In the practice of this invention. an sacetylenic the preparation of synthetic compounds having carbinol,

vitamin A activity. This publication disclosed that a compound having the following formula: ('33! H1 o11:011-c-'oo o'Ho=oHoHi-X CHa CH2 6H CH3 I (EH3 1H: OH: 2 cH=oH-c-on=cH-oH, o=oH oHi-ocH, q, I

OH in whichXis OR or H2 -CH:

0 Hg P:

could be prepared by catalytic reduction of and Bus a" hydrocarbon radical, may be prepared an acetylenic compound prepared by reacting byeitlierof'two routes. wethynyI-p-ionoI with aGrignara reagent and Intheflrst andpreferred'rout'e u-ethynyl-pionol is reacted with a reagent such as a metal alkyl in which the metal is a member of the first group, preferred reagents being CHsLi and C4H9Li; or a metal alkyl in which the metal is a member of the second group such as zinc or magnesium. When zinc is the metal, the reagent may be a zinc dialkyl such as (CH3)2Z1'1 or an alkyl zinc iodide such as CI'hZnI; and when magnesium is the metal, the reagent may be dialkyl magnesium such as (C2H5)2Mg or a Grignard reagent such as CzHsMgBr. The Grignard reagent is preferred.

The reagent may be considered as having the following general formula: (R').1:MY, in which R is a hydrocarbon radical, such as methyl, ethyl, benzyl, and the like; a: is an integer not greater than two; M is a metal having a valence not greater than two, and Y is a halogen if a: is one and the valence of the metal is two; but Y is nonexistent if M is a metal having a valence of one or if M is a metal having a valence of two and a: is two.

a-Ethynyl-B-ionol may be prepared in a number of difierent ways and in particular by reacting B-ionone with calcium or lithium acetylide in an inert solvent as set forth in my U. S. Patent No. 2,425,201, filed September 11, 1945, and issued August 5, 1947; and in my copending application Serial No. 655,607, filed March 19, 1946, now U. S. Patent No. 2,472,310.

The product of this first reaction is represented by the formula:

CH; CH

a H2 CH=CHCCEC-MYR' OMYR' Ha -CHI Compound II H2 in which M, Y, and B have the same significance as above; but in which Y and R. are nonexistent if M is a metal having a valence of one, R is nonexistent if M is a metal having a valence of two and Y is a halogen, and Y is nonexistent if M is a metal having a valence of two and R is a hydrocarbon radical. In the preferred embodiment MY is MgBr and R is nonexistent or M is a metal having a valence of one and Y and R, are nonexistent. In the single preferred practice or embodiment MY is MgBr and R is nonexistent. The preparation of this compound is described in my copending U. S. application Serial No. 657,912, filed March 28, 1946, now abandoned. Compound II is reacted with an ether or ester of a 1,4 halohydrin of isoprene represented by the formula in which Z is a halogen, X is OR or ets and R is a hydrocarbon radical and in which, in the preferred form, X is OCH3. The preparation of this reagent is described in my copending U. S. applications Serial No. 633,873, filed December 8, 1945, now U. S. Patent No. 2,541,091, and

Serial No. 633,874, filed December 8, 1945, now

mide, cuprous chloride, cuprous iodide, cuprous cyanide, cupric chloride, cobalt chloride, ferric chloride, and cupric bromide are satisfactory catalysts, but anhydrous cupric chloride is preerred. The product of this reaction, before hydrolysis, is present in solution and corresponds to the formula in which M, Y, R, and X have the same meaning as above and in which in the preferred form MY is MgBr, R is nonexistent, and X is OCI-I3.

Hydrolysis of the reaction mixture containing Compound III in solution may be accomplished by any of the usual methods used for the hydrolysis of a Grignard reaction mixture, such as treating with dilute acids, Water, or preferably with a solution of a Water soluble ammonium salt which has been made slightly alkaline, pH 7.5-9.0, by the addition of aqueous ammonium hydroxide. Upon hydrolysis of Compound III, Compound I is produced.

After the hydrolysis is complete, it is necessary to remove unreacted reagent from the reaction mixture, and for this purpose, a base is employed. Inorganic bases such as alcoholic sodium hydroxide and potassium hydroxide or organic bases such as diethyl amine may be used.

The following equations illustrate the preferred process for the preparation of Compound 1:

CH: CH:

H2 "CH3 Compound 11 CH: Compound II ZCHz( I=CHCHzX CH3 CH3 CH3 CH3 Compound III hydrolysis Compound III CH3 CH3 CH: CH:

H2 CH:

Compound I An alternate procedure for preparing Compound I is to react the beforementioned reagent i z-omc=onomx with sodium, potassium, lithium, or calcium and then to react this with RMgZ, where Z is a halogen and R" is a hydrocarbon radical, to form an intermediary compound:

The acetylenic bond of Compound I may be reduced to a double bond; the resulting substance has the following structure:

Compound IV where X has the same significance as before.

In the conversion of Compound I to Compound IV, catalytic hydrogenation may be used, and in this case it has been found that poisoned palladium supported on calcium carbonate, Raney nickel, or poisoned Raney nickel are satisfactory. Raney nickel may be satisfactorily poisoned by a cadmium salt, a zinc salt which forms a soluble complex in methyl alcohol with an amine, piperidine, pyridine, thiourea, aminothiazoles, or a combination of zinc acetate and piperidine; however, Raney nickel poisoned by a combination of zinc acetate and piperidine is the preferred catalyst. It is also possible to reduce by chemical reagents, but catalytic hydrogenation is preferred.

In the following specific examples for carrying out the reactions outlined above, the preparation of Compound I by the preferred route will be used as illustrative, and the compounds will be referred to by numbers used in the above description.

The folowing examples are given merely to illustrate specific ways in which the invention may be practiced, and it is to be understood that the invention is not to be restricted or limited thereby.

6 EXAMPLE I Conversion of a-ethynyZ-s-ionol into its Grignard derivative One mole proportion (218 grams) of a-ethynylc-ionol was placed in a glass flask. Then there were added thereto about 600 grams of anhydrous ethyl ether which dissolved said u-ethynylc-ionol. This solution was continuously agitated or stirred while there were gradually added thereto two mole proportions of a Grignard reagent and in this illustration 267 grams of CzHsMgBr dissolved in 700 cc. of anhydrous ethyl ether. After completion of this addition, the mixture was heated to boiling while continuously stirred and in a constant state of agitation and was maintained in this state of boiling under a reflux condenser for a period of approximately thirty minutes, whereby a novel reaction product which was dissolved in said ethyl ether was produced. It may be isolated therefrom in any convenient manner and has the following formula:

I OMgBr Hg CH3 EXAMPLE II Conversion of e-ethynyl-p-ionol into its lithium derivative The same procedure as that set forth in Example I was followed except that two moles (44 grams) of methyl lithium were substituted for the ethyl magnesium bromide of Example I. The resultant reaction product had a low solubility factor in ethyl ether and separated out as a crystalline solid and has the following formula:

EXAIMPLE III Conversion of a-eth11nyl-/3-ionol into its Grignard derivative The same procedure as that set forth in Example I was followed except that two moles (7.50 grams) of methyl magnesium chloride were substituted for the ethyl magnesium bromide of Example I. The resultant reaction product had a low solubility factor in ethyl ether and sep arated out as a crystalline solid and has the following formula:

CH3 CH3 J- CH=CH'-( 3CEC-Mg c1 EXAMPLE IV Conversion of a-ethynyl-c-ionol to its zinc iodide derivative The same procedure as that set forth in Erample I was followed except that two moles (415 grams) of methyl zinc iodide were substituted for the ethyl magnesium bromide of Example I.

This novel reaction product was partially soluble in ethyl ether and maybe isolated therefrom in any convenient manner and has the following formula:

OH: CH:

(1 H; H. GH=CHCCEC-Znl 02:11 H: CH:

EXANIPLE V Condensation of a-ethynyZ-p-ionol double Grinnard with 1-chloro-2-methyl-4-methoxybutene-Z to form (Compound IIImethoa:y)

To the reaction mixture from Example I containing Compound II in the preferred form and which had been allowed to cool to room temperature was added one mole proportion of the methyl ether of the 1,4 chlorohydrin of isoprene, followed by the addition of approximately 5 grams of anhydrous cupric chloride as a catalyst. The mixture was stirred under a reflux condenser and heated to boiling and kept at a boiling temperature under reflux four to eight hours, and then allowed to cool to room temperature and stirred for fifteen hours. At this point two layers were formed.

Cuprous bromide may be used to catalyze this condensation. When cupric chloride was used, a series of color changes from dark red to yellow occurred within the first few minutes, but when cuprous bromide was used, there were no color changes, but a gradual solution of the solid occurred. After approximately three-fourths of an hour, a heavy lower liquid layer was formed. Refiuxing with stirring was continued at room temperature for fifteen hours in either case. .By this time the lower liquid layer had changed to a tacky reddish mass.

EXAMPLE VI Hydrolysis of Compound III (methoxy) to obtain Compound I' (methoxy) The reaction product from Example V was hydrolyzed by first chilling the stirred fiask contents to 40 C. and adding slowly and cautiously 150 cc. of 30% aqueous ammonium chloride. The reaction mixture was allowed to come up slowly to room temperature with stirring and was then stirred until all solid matter had dissolved.

The hydrolysis may be made with aqueous acetic acid, and in this case, the reaction prodnot from Example V was cooled to C., and

CJI

acid was completed. In either case the mass was allowed to come to room temperature and was filtered. The filtrate separated into two layers, an aqueous layer and an ether layer. The ether layer was separated from the aqueous layer and washed with water and then with sodium bicarbonate solution to neutralize any residual acetic acid.

A 5% aqueous solution of ammonium acetate may also be used to hydrolyze the reaction product from Example V by following the same conditions as when aqueous acetic acid is used.

The neutral reaction product obtained by the hydrolysis was treated to remove therefrom any unreacted methyl ether of the 1,4 chlorohydrin of isoprene. This was done by adding an organic base and in this example by adding diethyl amine, 73 grams (1 mole), to the wet etheral solution of the crude condensation product as directly obtained from the hydrolysis. The amine being higher boiling than ether, the ether was removed by distillation at atmospheric pressure. This solution was allowed to stand at room temperature for eight to twenty-four hours and was then poured into a large volume of water, whereupon liquid oily particles separated out and were extracted with ethyl ether which dissolved the same. This ether solution was separated and removed from the aqueous portion of the mix and was then washed with water several times, and finally with an aqueous solution of sodium carbonate. The solution was dried with anhydrous potassium carbonate or other suitable drying agent and filtered; the filtrate was recovered and concentrated under vacuum at room temperature. The concentrate consisted essentially of Compound I and was distilled under high vacuum at C. to C. and 0.001 mm. of mercury pressure. This material had a refractive index at 20 C. of 1.5116 and showed absorption in the ultra violet with a maximum at 2370 A and a molecular coefficient of extinction at this wave length of 6,026. A formula such as that of Compound I has a theoretical value for carbon of 79.69% and of 10.19% for hydrogen; 79.63% carbon and 10.22% hydrogen were found on analysis.

It has been found that if the wet ether solution is concentrated without first adding a base, the moisture present eventually hydrolyzes some unreacted methyl ether of the 1,4 chlorohydrin of isoprene which is present in excess, and the free hydrogen chloride thus formed, even in traces, causes partial dehydration of the condensation product. By concentrating in the presence of an amine such hydrolysis may be prevented since any free hydrogen chloride formed is immediately neutralized by the amine present and thus prevents dehydration. ,On small experiments where the time required to remove the ether is relatively short, the presence of the amine is not necessary since the ether is fully removed before any of the chlorohydrin has a chance to hydrolyze and the product is treated at that point to remove the unreacted chlorohydrin as indicated below. However, on larger experiments, the time required to remove the ether is naturally much longer, and the chlorohydrin has a chance to hydrolyze. Under such conditions there must always be amine present or some other base to neutralize any hydrogen chloride that may be formed.

EXAMPLEVII Hydrogenation of Compound I (methoxy) by the use of poisoned palladium as a catalyst to produce Compound IV (methoxy) Compound I (methoxy) obtained by proceeding as in Example VI was dissolved in five to ten times its volume of anhydrous methanol containing .07 gram of zinc acetate and 10 cc. of diethyl amine per cc. of the said solution of Compound I in methanol. To this solution was then added 10 grams of powdered activated charcoal Norite" containing one gram of palladium metal uniformly distributed on its surface. This mixture was shaken to thoroughly distribute the components with respect to each other;' The entire mixture was then shaken under an atmosphere of hydrogen gas at atmospheric pressure. A small amount of hydrogen was absorbed in this step. To this mixture were added 30 grams of calcium carbonate powder containing 0.36 gram of palladium hydroxide uniformly distributed on its surface, and this mixture was again subjected to shaking in an atmosphere of hydrogen at atmospheric pressure. Absorption of hydrogen was measured continuously as it was being added. When one mole of hydrogen had been absorbed, this operation was stopped and the mass was filtered; the filtrate was recovered and consisted essentially of a novel compound dissolved in methanol and having the following general formula:

This methanol solution was poured into a large volume of water which dissolved the methanol and separated the oil therefrom. To this mass there was added ethyl ether which dissolved the oil. This mass separated into two layers, an ether layer and an aqueous layer. The ether layer was separated from the aqueous layer and washed several times with water; it was then dried with potassium carbonate or any other suitable drying agent, filtered, and the filtrate was recovered and concentrated under vacuum at room temperature. The concentrate was then subjected to high vacuum distillation. The product distilled at 105 C. to 115 C. at 0.001 of mercury pressure. The fraction distilling at the above temperature range weighed 260 grams. This fraction has carbon and hydrogen values corresponding to the calculated values of a compound having the formula of Compound IV (methoxy). Calculated carbon=79.19%, found: 79.36%; calculated hydrogen=10.76%, found: 10.73%. This fraction is a golden yellow viscous liquid whose ultra-violet spectrum shows an absorption band with a maximum at 2360 A and a molecular coeficient of extinction at this wave length of 6,500; it has an index of refraction at 20 C. of 1.5087. It shows the same growthpromoting properties in vitamin A deficient animals as does natural vitamin A.

EXAMPLE VIII Hydrogenation of Compound I (memory) by the,

use of poisoned Raney nickel as a cataZg st'to produce Compound IV (methory) The crude condensation product from Example VI was dissolved in five to ten times its volume of methanol and 2 cc. of pyridine and 6 grams of wet Raney nickel paste (Gilman Paint and Varnish Company) was then added. This mixture was shaken under hydrogen until the theoretical amount had been absorbed. After removal of the catalyst by filtration, the orange lected and this was Compound IV (methoxy), a pale yellow, mobile liquid having a refractive index at 25 C. of 1.5070.

Another reduction of the crude condensation product of Compound I to Compound IV was made in the same way as above using 150 cc. of

.methyl alcohol as the solvent, 5 grams of Raney nickel as the catalyst and a combination of 5 cc. piperidine and 300 mg. of zinc acetate as the poison for the catalyst. This resulted in a product having the same physical properties as shown above; the yield was also approximately the same.

EXAMPLE IX periodof onehour, were added two grams of cuprous bromide. The black color of the solution disappeared immediately, and the color was then light yellow. Eighteen grams of the acetoxy compound, in 20 cc. of ether, were added to the Grignard over a period of about ten minutes, and a second heavy layer appeared within a very short time after the addition was complete. The

solution was stirred under nitrogen for eighteen hours and then cooled to -20 C. A saturated solution of ammonium chloride was carefully added, and the solution was then allowed to come up to room temperature. The solution was filtered, washed with water, then with ether and ammonium chloride aqueous solution alternately several times. The solution was again filtered, and the ether layer concentrated under vacuum. The residual oil was dissolved in 50 cc. of ethyl alcohol and 50 cc. of diethyl ethanol amine. This solution was allowed to stand at room temperature for a period of two days under nitrogen and in the dark. The dark opaque reaction mixture was poured into several times its volume of brine solution and extracted with petroleum ether. The petroleum ether layer was washed with dilute acetic acid and then with water and finally with sodium bicarbonate solution. The solution was dried over potassium carbonate and concentrated under vacuum. The product of this reaction has the following formula:

EXAMPLE X Reduction of Compound I (acetory) The concentrate obtained from Example X was dissolved in cc. of t-butyl alcoholl One gram of catalytic material consisting of palladium on charcoal wherein 10% of the composition palladium, 2 cc. of water, and 10 cc of diethyl amine was added to the concentrate as a catalyst. The concentrate plus the catalyst mixture was shaken in the presence of hydrogen until an amount of hydrogen slightly in excess of the theoretical amount required to reduce an acetylenic bond to an ethylenic bond had been absorbed. The catalyst was then filtered off, and the resulting filtrate was poured into brine. This mixture was extracted several times with ether, washed well with water, and the ether solution was dried over potassium carbonate. The ether solution was filtered and concentrated under vacuum and finally distilled at 10- mm. Three fractions were taken.

The first fraction came over at 60 C. to 105 C. and had a refractive index at 27.7 C. of 1.5128. The second fraction came over at 105 C. to 110 C. and had a refractive index at 27.7 C. of 1.5278. The third fraction came over at 110 C. to 150 C. and had a refractive index at 27.7 C. of 1.5390. The third fraction represents the reduced product and is represented by the following formula:

CH3 CH3 Compound IV (acctoxy) H2 in which X is selected from the group consisting of OR and and R is a lower alkyl radical, to produce a compound of the formula CH3 CH2 wherein X has the same significance as above.

2. The method comprising hydrogenating a compound of the formula CH3 CH3 in which R is a lower alkyl radical, to produce a compound of the formula CH: CH;

in which R is a lower alkyl radical.

12 3. The method comprising hydrogenating a compound of the formula CH: CH;

(311a (IE3 IE1 CH=CH(]1CEC-CH:C=CHOHz-O-CH;

OH H CH| Hz to produce a compound of the formula:

CH3 CH3 a (311: 112 CH=CHC-CH=CH-OHa-C=CHCHz-O-CH:

1 OH H: CH:

4. The method comprising reacting a-ethynylfl-ionol with a metallo-organic compound of the class consisting of lithium, magnesium, and zinc alkyls and magnesium and zinc alkyl halides, in which each alkyl is of low molecular weight, to produce a compound in which the hydrogen of the hydroxyl group and the hydrogen of the acetylenic group are removed and the oxygen of the hydr xyl group and the terminal carbon of the acetylenic group are each bound to a metal.

5. A method according to claim 4 in which the metallo-organic compound is a magnesium alkyl halide.

6. A method according to claim 4 in which the metallo-organic compound is methyl lithium.

7. A method according to claim 4 in which the metallo-organic compound is ethyl magnesium bromide.

8. The method comprising reacting a-ethynylfi-ionol with a metallo-organic compound of the class consisting of lithium, magnesium, and zinc alkyls and magnesium and zinc alkyl halides, in which each alkyl is of low molecular weigh to produce a compound in which the hydrogen of the hydroxyl group and the hydrogen of the acetylenic group are removed and the oxygen of the hydroxyl group and terminal carbon of the acetylenic group are each bound to a metal; and reacting the reaction product with a compound of the formula CH: Z-CHz( 3=CHCHzX wherein Z is halogen, X is selected from the group consisting of-OR. and

and 'R is a lower alkyl radical, to produce a compound of the formula in which X has the same significance as above.

9. A method according to claim 8 in which Z is chlorine.

10. A method according to claim 8 in which X is -OR and R is a methyl radical.

11. The method comprising reacting a-ethynylp-ionol with a metallc-organic compound of the class consisting of lithium, magnesium, and zinc alkyls and magnesium and zinc alkyl halides, in which each alkyl is of low molecular weight, to produce a compound in which the hydrogen of the hydroxyl group and the hydrogen of the acetylenic group are removed and the oxygen of the hydroxyl group and the terminal carbon of the acetylenic group are each bound to a metal; reacting the reaction product with a compound of the formula and R is a lower alkyl radical, to produce a compound of the formula in which X has the same significance as above; and hydrogenating the acetylenic loond to produce a compound of the formula in which X has the same significance as above.

12. A method according to claim 11 in which the metallo-organic compond is a magnesium alkyl halide.

13. The method comprising reacting a-ethynylfi-ionol with a metallo-organic compound of the class consisting of lithium, magnesium, and zinc alkyls and magnesium and zinc alkyl halides, in which each alkyl is of low molecular weight to produce a compound in which the hydrogen of the acetylem'c group are removed and the oxygen of the hydroxyl group and the terminal carbon of the acetylenic group are each bound to a metal; reacting the reaction product with a compound of the formula 14 wherein Z is halogen, X is selected from the group consisting of -OR and n 5 O C R and R is a lower alkyl radical, to produce a compound of the formula CH: OH:

in which X has the same significance as above; hydrogenating the acetylenic bond to produce a compound of the formula in which X has the same significance as above; and dehydrating to produce a conjugated pentaene having vitamin A activity.

14. A method according to claim 13 in which the metallo-organic compound is a magnesium alkyl halide.

15. A method according to claim 13 in which Z is chlorine.

Kipping et al.: Chemistry and Industry," August 26, 1939. Vol. 58, page 802.

Oroshink: Jour. Am. Chem. 800., vol. 67 (1945), pages 1627, 1628.

Heilbron: "Jour. Chem. Soc. (London), 1948, page 387.

Claims (1)

1. THE METHOD COMPRISING HYDROGENATING A COMPOUND OF THE FORMULA